Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C=O.[ClH:11].[CH:12]1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][Cl:11])=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: c1ccccc1
Reactant: Cl
Agent: C=O
Product: Fc1ccc(SCCl)cc1
Yield: 99.8 %

Procedure:
This compound was prepared in the manner of Example 3.A., using 45.0 grams (0.35 mole) of a 4-fluorothiophenol, 13.5 grams (0.44 mole) of paraformaldehyde and 180 ml (1.8 moles) of concentrated hydrochloric acid in 90 ml of benzene. The residue was distilled under reduced pressure to give 61.9 grams (99.8%) of 4-fluorophenylthiomethyl chloride; b.p. 65° C./0.5 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCN1CCCCC1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCN1CCCCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and N-(2-aminoethyl)piperidine (63 mg, 0.39 mmol). The title compound was obtained as a solid (20 mg, 11% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, s), 8.83 (1H, m), 8.42 (1H, s), 3.32 (2H, m), 2.42 (3H, m), 2.35 (1H, m), 1.48 (4H, m), 1.37 (2H, m). MS m/z: 459.16, 461.15 [M+H]+.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](N(OC)C)=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([Li])[CH2:22][CH2:23][CH3:24].C(=O)=O.CC(C)=O.C(OCC)(=O)C>C1COCC1>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15](=[O:16])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [Li]CCCC
Reactant: CON(C)C(=O)Cc1ccc(OC2CCCCC2)cc1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCCC(=O)Cc1ccc(OC2CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of the 2-(4-cyclohexyloxy-phenyl)-N-methoxy-N-methyl-acetamide (149 mmol, 41.4 g) in anhydrous THF (150 mL) at −78° C. was added n-butyl lithium (1.6 M in hexanes, 298 mmol, 186 mL) dropwise over 45 minutes. The dry ice/acetone bath was replaced with an ice bath, and the reaction was stirred for an additional 30 min. TLC (30% ethyl acetate in hexanes) analysis indicated complete consumption of starting material. The reaction mixture was quenched by addition of saturated ammonium chloride (100 mL) at 0° C., further diluted with water (125 mL) and extracted with ethyl acetate (2×150 mL). The combined ethyl acetate layers were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in 6% ethyl acetate in hexanes and filtered through a 110 g SiO2 column. The column was eluted with 6% ethyl acetate in hexanes to provide 1-(4-cyclohexyloxy-phenyl)-hexan-2-one upon evaporation of solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][NH2:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:13]([CH:17]=2)[C:14]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:26]([O:25][CH3:24])[CH:27]=2)=[O:16])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: Cc1cc(Cl)cc(-c2cnc(N3CCOCC3)c(C(=O)O)c2)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(Cl)c3)cnc2N2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(3-chloro-5-methylphenyl)-2-morpholin-4-ylnicotinic acid (4-2, 2.8 g, 8.41 mmol) and 3,4-dimethoxybenzylamine (6.30 mL, 42.1 mmol) in DCM (42 mL) was added EDC (4.84 g, 25.2 mmol), HOBt (3.87 g, 25.2 mmol) followed by N-methylmorpholine (9.25 mL, 84 mmol) and the system was stirred at 25° C. overnight. The reaction mixture was partitioned between ethyl acetate and water, washed with saturated sodium bicarbonate and dried over magnesium sulfate. The reaction mixture was filtered, concentrated and triturated with diethylether to afford the title compound (4-3) as a bone powder. 1H NMR (400 MHz, CDCl3) δ 8.82 (m, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.49 (d, J=2.4 Hz, 1H), 7.35 (s, 1H), 7.16 (s, 1H), 6.90 (m, 2H), 6.84 (m, 1H), 4.56 (d, J=5.6 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.55 (m, 4H), 3.12 (m, 4H), 2.37(s, 3H). HRMS [M+H] C26H28ClN3O4 calc'd 482.1841, found 482.1847.
Reaction SMILES: B(Br)(Br)Br.[OH:5][C:6]1[C:15]2[C:10](=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH2:20][O:21]C)[C:7]=1[C:23]([NH:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=[O:24].O>C(Cl)Cl>[OH:5][C:6]1[C:15]2[C:10](=[C:11]([C:16]([F:17])([F:19])[F:18])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH2:20][OH:21])[C:7]=1[C:23]([NH:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=[O:24]
Reactant: COCc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)c1c(CO)nc2c(C(F)(F)F)cccc2c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A solution of 4 ml of boron tribromide in 30 ml of methylene chloride was added with stirring at -70° C. to a solution of 2.88 g of the product of Example 3 in 75 ml of methylene chloride and the mixture stood overnight with stirring while the temperature was allowed to rise to -20° C. The mixture was poured into 500 ml of ice and water and the mixture was stirred for 20 minutes and was vacuum filtered. The product was washed with water until the pH was 5 to 6 and was dried under reduced pressure at 100° C. The product was dissolved in refluxing dimethylformamide and the solution was cooled, iced and vacuum filtered. The product was washed with dimethylformamide and then with ether and dried under reduced pressure at 120° C. to obtain 2.3 g of 4-hydroxy-2-hydroxymethyl-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide melting at 280° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5](Br)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CS(C)=O>[CH2:5]([N:1]=[N+:2]=[N-:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
A mixture of sodium azide (7.6 g, 116.9 mmol), benzyl bromide (10 g, 58.4 mmol) in DMSO (80 mL) was stirred at room temperature for 18 h. The reaction mixture was then slowly poured into ice water and extracted with ether (3×200 mL). The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated, giving the title compound as a colourless oil (6.9 g, 88% yield).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[CH:8]2[CH:11]([CH3:22])[NH:12][CH:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH:7]2[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[CH:24](O)=O.C=O>[OH-].[Na+]>[CH2:1]([N:5]1[C:9](=[O:10])[CH:8]2[CH:11]([CH3:22])[N:12]([CH3:24])[CH:13]([C:14]3[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=3)[CH:7]2[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C2C(C)NC(c3ccc(C#N)cc3)C2C1=O
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: CCCCN1C(=O)C2C(C1=O)C(c1ccc(C#N)cc1)N(C)C2C
Temperature: 100 °C
Yield: 84.9 %

Procedure:
A mixture of 2.84 g of (1RS,3SR,3aRS,6aSR)-4-(5-butyl-3-methyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl)-benzonitrile, 85% formic acid (4.9 g, 90 mmol) and 35% formalin solution (2.6 g, 30 mmol) were heated to 100° C. for 5.5 hours. After cooling 1N NaOH (50 ml) was added and the mixture was extracted four times with dichloromethane. The organic phase was concentrated and the residue was separated chromatographically (hexane/ethyl acetate 3:1+1% triethylamine). 2.52 g of (1RS,3SR,3aRS,6aSR)-4-(5-butyl-2,3-dimethyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl)-benzonitrile (85%) were isolated as a colourless oil. EI-MS: 325 (M+, 8); 310 (95); 223 (10); 183 (24); 171 (40); 157 (10); 143 (9); 70 (15); 56 (17); 43 (100).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[C:23]([N:25]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:22]3[N:42]=[CH:43][CH:44]=[C:21]3[N:20]=2)[CH2:15][CH2:14]1)=[O:12]>C(#N)C>[CH3:9][O:10][C:11]([CH:13]1[CH2:14][CH2:15][CH:16]([C:19]2[CH:24]=[C:23]([N:25]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[N:22]3[N:42]=[CH:43][C:44]([I:1])=[C:21]3[N:20]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Solvent: CC#N
Product: COC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
N-Iodosuccinimide (811 mg, 3.6 mmol) was added into a solution of 4-{7-[bis-(2-trimethylsilanyl-ethoxymethyl)-amino]-pyrazolo[1,5-a]pyrimidin-5-yl}-cyclohexanecarboxylic acid methyl ester (1.75 g, 3.27 mmol) in acetonitrile (25 mL). The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and purified via silica gel chromatography (0% to 30% ethyl acetate in hexanes gradient) to yield the title compound (1.79 g, 82.8% yield) at clear oil. LC-MS: 661 [M+H].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1.[CH2:26]([NH2:31])[CH2:27][CH2:28][CH2:29][CH3:30]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:31][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: CCCCCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Product: CCCCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol), and pentylamine (2 ml) the subtitle compound was obtained (289 mg, 100%). MS 402 m/z (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][NH:23][CH2:24]3)=[CH:19][CH:18]=2)[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]([CH3:30])[CH2:24]3)=[CH:19][CH:18]=2)[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=c1cc(OCc2ccccc2)ccn1CCc1ccc2c(c1)CNCC2
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCc2ccc(CCn3ccc(OCc4ccccc4)cc3=O)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 150 mg (0.42 mmol) 4-benzyloxy-1-[2-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1H-pyridin-2-one (example 24.2) in 5.0 mL THF is added 68 μL (0.83 mmol) aqueous 37% formaldehyde solution. The mixture is acidified with 3 drops of acetic acid and then 97 mg (0.46 mmol) sodium triacetoxy-borohydride is added. The reaction mixture is stirred 2 h at RT and additional 68 μL (0.83 mmol) aqueous 37% formaldehyde solution and 97 mg (0.46 mmol) sodium triacetoxy-borohydride are added. The reaction mixture is stirred overnight and additional 68 μL (0.83 mmol) aqueous 37% formaldehyde solution and 97 mg (0.46 mmol) sodium triacetoxy-borohydride is added and the reaction mixture is stirred additional 48 h at RT. The mixture is poured into aqueous 10% Na2CO3-solution, the layers are separated and the aqueous phase is extracted with DCM. The combined organic phase is washed a few times with water, dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[N+]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22](Cl)=[CH:21][C:20]=1[CH2:27][C:28]([N:30]([CH3:49])[C@@H:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=2)CC[C@H:32]1[N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=[O:29])([O-])=O.[CH3:50][S:51](C1C=CC(CC(O)=O)=CC=1)(=[O:53])=[O:52].N1C=CC=CC=1>>[CH3:50][S:51]([C:23]1[CH:22]=[CH:21][C:20]([CH2:27][C:28]([N:30]([CH3:49])[C@@H:31]([C:40]2[CH:35]=[CH:36][CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=2)[CH2:32][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:29])=[CH:19][CH:24]=1)(=[O:53])=[O:52].[ClH:25]
Reactant: CN(C(=O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-])[C@@H]1c2cc([N+](=O)[O-])ccc2CC[C@H]1N1CCCC1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CN(C(=O)Cc1ccc(S(C)(=O)=O)cc1)[C@H](CN1CCCC1)c1cccc([N+](=O)[O-])c1
Product: Cl

Procedure:
This compound was prepared via the general DCC/pyr coupling procedure from 8 (0.5138 g, 2.061 mmol), 4-methylsulfonylphenylacetic acid (0.8825 g, 4.119 mmol), DCC(0.8771 g, 4.251 mmol), and pyridine (0.34 mL, 4.245 mmol). The crude product was gravity column chromatographed eluting with CHCl3:2% NH3 before it was converted to the HCl salt with 1.0 M HCl in Et2O and crystallized from MeOH to yield 14 HCl.(0.4695 g, 47%): m.p. (HCl salt) 276-277° C.; 1H NMR (HCl salt, DMSO-d6) δ2.0 (br s, 4H, —CH2CH2—), 2.92 (s, 3H, —NCH3), 3.2 (s, 3H, —SO2CH3), 3.2-4.3 (complex, 8H, 4 —CH2—), 6.25 (m, 1H, —CH—), 7.61 (d, J=7.2 Hz, 2H, aromatic), 7.75 (m, 2H, aromatic), 7.89 (d, J=7 Hz, 2H, aromatic), 8.12 (s, 1H, aromatic), 8.25 (m, 1H, aromatic). MS(FAB) m/z 446. Anal. (C, H, N) C22H27N3O5S HCl.
Reaction SMILES: C(Cl)CCl.[C:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([OH:21])=O)[CH2:14][CH2:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][NH2:30])=[N:27][CH:28]=1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:8]([O:7][C:5]([N:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]([NH:30][NH:29][C:26]2[CH:25]=[CH:24][C:23]([F:22])=[CH:28][N:27]=2)=[O:21])[CH2:16][CH2:17]1)=[O:6])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Reactant: NNc1ccc(F)cn1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)NNc2ccc(F)cn2)CC1
Yield: 80 %

Procedure:
EDC (543 mg, 2.83 mmol) was added portionwise to a solution of 2-(4-Boc-1-piperazinyl)acetic acid (576 mg, 2.36 mmol), 5-fluoro-2-hydrazinyl-pyridine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 0.30 g, 2.36 mmol) and HOBt (32 mg, 0.24 mmol) in dry DCM (15 mL) at RT and stirred for 16 h. The solution was diluted with DCM (20 mL), washed with water (2×20 mL) and dried (Na2SO4). The solvent was evaporated to give the title compound as an off-white solid (667 mg, 80%). LCMS (Method 1): Rt 1.99 min, m/z 354 [MH+].
Reaction SMILES: C(N(CCC)CCC)CC.Cl[C:12]1[N:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=2)[N:13]=1.[CH2:26]([N:28]1[CH:43]=[CH:42][C:31]2[N:32]=[C:33]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[N:34]=[CH:35][C:30]=2[C:29]1=[O:44])[CH3:27]>C(O)CC(C)C>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:24][CH3:25])[N:13]=[C:12]([N:39]1[CH2:38][CH2:37][N:36]([C:33]3[N:34]=[CH:35][C:30]4[C:29](=[O:44])[N:28]([CH2:26][CH3:27])[CH:43]=[CH:42][C:31]=4[N:32]=3)[CH2:41][CH2:40]1)[N:21]=[CH:20]2
Reactant: CCn1ccc2nc(N3CCNCC3)ncc2c1=O
Reactant: COc1cc2cnc(Cl)nc2cc1OC
Agent: CCCN(CCC)CCC
Solvent: CC(C)CCO
Product: CCn1ccc2nc(N3CCN(c4ncc5cc(OC)c(OC)cc5n4)CC3)ncc2c1=O
Yield: 92.9 %

Procedure:
Tri-n-propylamine (0.43 g) was added to 0.67 g of the 2-chloro-6,7-dimethoxyquinazoline synthesized in Referential Example 91 and 0.78 g of the 6-ethyl-2-piperazinopyrido[4,3-d]pyrimidine-5(6H)-one synthesized in Referential Example 14. Using 5 g of isoamyl alcohol as a solvent, they were heated and reacted for 10 hours under reflux. The resultant crystals were collected by filtration and then washed first with ethyl acetate and then with hexane. They were dried to obtain 1.24 g of the above-identified compound as white crystals (yield: 92%).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([C:19]#[C:20][C:21]2[S:22][C:23]([C:26]([OH:28])=O)=[CH:24][N:25]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.FC(F)(F)C(O)=O>O1CCCC1.CCOC(C)=O>[C:13]1([C:19]#[C:20][C:21]2[S:22][C:23]([C:26]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])=[CH:24][N:25]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1cnc(C#Cc2ccccc2)s1
Reactant: C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1cnc(C#Cc2ccccc2)s1)N1CCCCC1
Reaction time: 1 h
Yield: 61.7 %

Procedure:
N,N-Carbonyldiimidazole (790 mg, 4.87 mmol) (Fluka Chemie AG) was added to a solution of 2-phenylethynyl-thiazole-5-carboxylic acid (1.00 g, 4.36 mmol) [Intermediate 1] in tetrahydrofuran (17.4 mL) and stirred for 60 minutes. Piperidine (3.03 g, 35.6 mmol) and trifluoroacetic acid (295 μL, 3.83 mmol) were added and the mixture was stirred for 20 hours. The yellow solution was diluted with 150 mL of EtOAc and washed with 3.7 M HCl solution (5×30 mL), water (1×30 mL), 1.0 M K2CO3 (4×30 mL), water (2×30 mL), brine (1×30 mL), dried (Na2SO4) and concentrated to give a light tan solid (94% pure by LC/MS). The sample was further purified by silica gel chromatography over a 40 g SiO2 column using a gradient elution from 25% EtOAc in hexanes to 30% EtOAc in hexanes over 30 minutes to give title compound (2-phenylethynyl-thiazol-5-yl)-piperidin-1-yl-methanone (797 mg, 62%) as a light yellow powder. 1H NMR (300 MHz, CDCl3) δ 7.94 (s, 1H), 7.63-7.59 (m, 2H), 7.46-7.36 (m, 3H), 3.69-3.67 (m, 4H), 1.78-1.62 (m, 6H). LCMS (Method 1), RT=1.41. Calculated [M+H]+=297; Observed [M+H]+=297.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[C:4]([SH:10])=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1>C(O)C.O.C(OCC)(=O)C>[N+:23]([C:22]1[C:17]([S:10][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[C:7]([OH:9])=[O:8])=[N:18][CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: O=C(O)c1ccccc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1Sc1ncccc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
To a suspension of 11.67 g of 2-thiobenzoic acid in a mixture of 32 ml of ethanol and 11 ml of water is added portionwise 12.72 g of solid sodium bicarbonate. After the complete addition, the mixture is stirred for 15 minutes and 10.0 g of 2-chloro-3-nitropyridine added portionwise. The mixture is refluxed for 2 hours, cooled and then concentrated in vacuo. The residual aqueous solution is diluted with 15 ml of water, acidified with 2N HCl and extracted twice with 250 ml of ethyl acetate. The extract is concentrated under vacuum to give a yellow solid residue. The residue is dissolved in a minimum of ethyl acetate by heating on a steam bath. The solution is cooled overnight and filtered. (2.5 g of starting material). The filtrate is concentrated, chilled and filtered to give 12.5 g of 2-(3-nitro-2-pyridinylthio)benzoic acid as a yellow solid. The preceding compound (5.0 g) and 0.75 g of Pd/C in 60 ml of ethanol is shaken in a Parr hydrogenator under 45 psi of hydrogen for 18 hours. The mixture is filtered through diatmoaceous earth and the filter cake washed with 200 ml of dichloromethane. The combined filtrate is evaporated in vacuo to give a solid. The solid is triturated with ethanol and filtered to give 3.6 g of yellow solid. This solid (3.0 g) is again hydrogenated with Pd/c (0.50 g) in 50 ml of ethanol and 30 ml of acetic acid under 45 psi of hydrogen for 18 hours. The mixture is filtered through diatomaceous earth and the filter cake washed with methanol. The combined filtrate is concentrated in vacuo to give 1.6 g of solid. This solid in 25 ml of N,N-dimethylformamide is again reduced with 0.80 g of Pd/C under 45 psi of hydrogen to give 0.57 g of solid. Recrystalization from ethyl acetate gives 0.28 g of 2-(3-amino-2-pyridinylthio)benzoic acid. The preceding compound (0.20 g) is heated in 2-hydroxypyridine at 170° C. to give 5,6-dihydropyrido[2,3-b][1,4]benzothiazepine as a yellow solid. The preceding compound is reacted with borane-dimethylsulfide as described for Reference Example 17 to give the product as a solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN1C(=O)CCC1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: NCCNc1ccccn1
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(CNC(=O)c2cc(NCCNc3ccccn3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and (2-aminoethyl)-2-pyridinylamine (88 mg, 0.64 mmol) were suspended in 2 mL of NMP and irradiated (microwave) as follows: 180° C. for 30 min, 200° C. for 30 min, 220° C. for 30 min, 230° C. for 30 min and then 240° C. for 1 h. After cooling to room temperature, some of the solvent was removed in vacuo and the residue was purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH, gradient 0 to 90:10:1). The collected solid was partitioned between water and EtOAc/toluene (1:1) and then extracted twice with DCM/isopropanol. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated in vacuo to afford a dark brown oil. After drying under vacuum overnight, the residue was again purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH (gradient 0 to 90:10:1). The collected solid was suspended in EtOH, sonicated, and filtered. The solid was further washed with EtOH/DCM, filtered, and dried in vacuum-oven for 2 days. The final product was collected as 47 mg (45%). LCMS E-S (M+H)=475.0 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (br. s., 1H) 8.47 (t, J=5.05 Hz, 1H) 7.97 (dd, J=4.93, 1.14 Hz, 1H) 7.85 (s, 1H) 7.32-7.39 (m, 2H) 6.65 (s, 1H) 6.61 (t, J=5.43 Hz, 1H) 6.46-6.51 (m, 2H) 5.89 (s, 1H) 4.97 (quin, J=6.69 Hz, 1H) 4.32 (d, J=5.05 Hz, 2H) 3.49 (dt, J=15.28, 5.62 Hz, 4H) 2.21 (s, 3H) 2.13 (s, 3H) 1.44 (s, 3H) 1.43 (s, 3H).